Inflammatory bowel diseases are characterized by intestinal inflammation, increased mucosal cytokines and compromised epithelial barrier function. Epithelial barrier function is regulated by a series of intercellular junctions that encompass the tight junction (TJ), adherens junction (AJ) and desmosomes (DMs). It is now evident that intercellular junctions are highly dynamic structures and their component proteins actively participate in regulating epithelial homeostasis. Mucosal inflammation perturbs intercellular junctions and epithelial homeostatic properties thereby resulting in epithelial barrier compromise. Our knowledge of the molecular basis of intercellular junction protein cross-talk, epithelial homeostasis and compromised epithelial barrier in intestinal inflammation is however very limited. Thus the overall goals of this proposal are to identify mechanisms by which intercellular junction proteins control epithelial homeostasis and barrier function and determine the influence of inflammation on epithelial barrier compromise. We will specifically examine the role of DM cadherins and TJ claudin proteins in regulating the intestinal epithelial barrier. The influence of pro- inflammatory cytokines, IFNg and TNFa on such regulatory processes will be determined. In addition to gaining insights into the molecular basis of intestinal epithelial barrier regulation, these studies will provide new ideas for the development of therapeutic agents that promote the intestinal epithelial barrier function and reduce mucosal inflammation. These studies will also provide insight into strategies of transiently perturbing the epithelial barrier for therapeutic drug/vaccine delivery and cancer therapy. PUBLIC HEALTH RELEVANCE: The epithelial lining of the gastrointestinal tract forms a regulated selective-permeable barrier permitting the uptake of luminal nutrients while restricting pathogen and toxin access to underlying tissue compartments. Intercellular junctions play a pivotal role in this barrier regulation. This proposal seeks to identify the molecular basis by which intercellular junction proteins control barrier function in health and disease. These studies will not only advance our understanding of barrier regulation, but will aid in the development of therapeutic agents that promote barrier function and reduce inflammation or on the converse increase permeability for drug/vaccine delivery.